This Program Project application has as its central theme, modulation of innate and adaptive immunity by host and microbial factors in the development of respiratory immunity against potential agents of bioterrorism. The Program projects share a common focus on 1) respiratory immunity to Yersinia pestis and poxviruses; 2) relating the quality or magnitude of an innate response to those in subsequent adaptive response; 3) the role of cytokines in the control of innate and adaptive responses; 4) the regulation of dendritic cell maturation and function; and 5) the impact of modulating TLR signaling on the generation of protective immunity to Y. pestis and poxviruses. These areas are explored in the context of assessing flagellin, a novel adjuvant, two viral vaccine vectors, SV5 and VSV, and the mechanism by which vaccinia virus suppresses the CD8+ T cell response. In Project 1, we will determine the mechanims(s) for the adjuvant effect of the TLR agonist, flagellin, and establish optimal conditions for its use in the development of protective respiratory immune responses against Y. pestis and poxviruses. In Project 2, we will investigate the mechanisms and efficacy of a viral vaccine vector, paramyxovirus simian virus 5 (SV5), in the promotion of adaptive immunity against Y. pestis and poxviruses, as well as analyze the effect of expressing specific TLR agonists in the context of the viral genome. In Project 3, we will define the features of vesicular stomatitis virus that are involved in the neurotropism of the virus and determine those elements that are essential for the promotion of an optimal level of innate and adaptive respiratory immunity to Y. pestis and poxviruses. The studies in Project 4 will investigate the mechanism by which intranasally instilled vaccinia virus suppresses the CD8+ T cell response in mice. These studies will address potential effects of the virus on the innate and adaptive phases of the anti-vaccinia response in the lung: the maturation and functions of dendritic cells; the cytokine environment; cytotoxic T cell function; and T cell anergy and deletion.